Molecular Cancer Research最新文献

{"title":"Single-Cell and Spatial Transcriptomics Reveal a Tumor-Associated Macrophage Subpopulation that Mediates Prostate Cancer Progression and Metastasis.","authors":"Shenglin Mei, Hanyu Zhang, Taghreed Hirz, Nathan Elias Jeffries, Yanxin Xu, Ninib Baryawno, Shulin Wu, Chin-Lee Wu, Akash Patnaik, Philip J Saylor, David B Sykes, Douglas M Dahl","doi":"10.1158/1541-7786.MCR-24-0791","DOIUrl":"10.1158/1541-7786.MCR-24-0791","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAM) are a transcriptionally heterogeneous population, and their abundance and function in prostate cancer is poorly defined. We integrated parallel datasets from single-cell RNA sequencing, spatial transcriptomics, and multiplex immunofluorescence to reveal the dynamics of TAMs in primary and metastatic prostate cancer. Four TAM subpopulations were identified. Notably, one of these TAM subsets was defined by the co-expression of SPP1+ and TREM2+ and was significantly enriched in metastatic tumors. The SPP1+/TREM2+ TAMs were enriched in the metastatic tumor microenvironment in both human patient samples and murine models of prostate cancer. The abundance of these SPP1+/TREM2+ macrophages was associated with patient progression-free survival. Spatially, TAMs within prostate cancer bone metastases were highly enriched within the tumor region, consistent with their protumorigenic role. Blocking SPP1 in the RM1 prostate cancer mouse model led to improved efficacy of anti-PD-1 treatment and increased CD8+ T-cell infiltration in tumor. These findings suggest that targeting SPP1+ TAMs may offer a promising therapeutic strategy and potentially enhance the effects of immune checkpoint inhibition in advanced prostate cancer.</p><p><strong>Implications: </strong>This study expands our understanding of the diverse roles of macrophage populations in prostate cancer metastases and highlights new therapeutic targets.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"653-665"},"PeriodicalIF":4.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12221797/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ANGEL2 Modulates Wild-type TP53 Translation and Doxorubicin Chemosensitivity in Colon Cancer.","authors":"Christopher August Lucchesi, Saisamkalpa Mantrala, Darren Tran, Neelu Batra, Avani Durve, Conner Suen, Jin Zhang, Paramita Ghosh, Xinbin Chen","doi":"10.1158/1541-7786.MCR-24-0702","DOIUrl":"10.1158/1541-7786.MCR-24-0702","url":null,"abstract":"<p><p>Multiple lines of correlative evidence support a role for angel homolog 2 (ANGEL2), a novel cancer-relevant RNA-binding protein, in the modulation of chemoresistance and survival of patients with cancer. However, to date, no study has determined a mechanism by which ANGEL2 modulates cancer progression, nor its role in chemoresistance. In this study, we demonstrate that loss of ANGEL2 leads to a substantial decrease in the key tumor-suppressor protein tumor protein p53 (TP53). We show that ANGEL2 directly interacts with eukaryotic translation initiation factor 4E (EIF4E), the rate-limiting protein in cap-dependent translation. This interaction abrogates the ability of the TP53 translation repressor RNA-binding motif protein 38 to interact with EIF4E, thereby enhancing TP53 translation. Loss of ANGEL2 in cancer cell lines resulted in increased two-dimensional and three-dimensional spheroid cell growth and resistance to doxorubicin and etoposide. With therapeutic potential, treatment with Pep7, a seven-amino-acid peptide derived from ANGEL2, rescued wild-type (WT) TP53 expression and sensitized cancer cells to doxorubicin. Together, we conclude that ANGEL2 modulates the EIF4E-RNA-binding motif protein 38 complex to enhance WT TP53 translation, and furthermore, the Pep7 peptide may be explored as a therapeutic strategy for cancers that harbor WT TP53 expression.</p><p><strong>Implications: </strong>Loss of ANGEL2 contributes to decreased WT TP53 translation promoting doxorubicin resistance, which can be rescued via an ANGEL2-derived peptide.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"585-596"},"PeriodicalIF":4.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12221813/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143573421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KSR2 Promotes Self-Renewal and Clonogenicity of Small Cell Lung Carcinoma.","authors":"Dianna H Huisman, Deepan Chatterjee, Robert A Svoboda, Heidi M Vieira, Abbie S Ireland, Sydney Skupa, James W Askew, Danielle E Frodyma, Luc Girard, Kurt W Fisher, Michael S Kareta, John D Minna, Trudy G Oliver, Robert E Lewis","doi":"10.1158/1541-7786.MCR-24-0546","DOIUrl":"10.1158/1541-7786.MCR-24-0546","url":null,"abstract":"<p><p>Small cell lung carcinoma (SCLC) tumors are heterogeneous, with a subpopulation of cells primed for tumor initiation. In this study, we show that kinase suppressor of Ras 2 (KSR2) promotes the self-renewal and clonogenicity of SCLC cells. KSR2 is a molecular scaffold that promotes Raf/MEK/ERK signaling. KSR2 is preferentially expressed in the ASCL1 subtype of SCLC (SCLC-A) tumors and is expressed in pulmonary neuroendocrine cells, one of the identified cells of origin for SCLC-A tumors. The expression of KSR2 in SCLC and pulmonary neuroendocrine cells was previously unrecognized and serves as a novel model for understanding the role of KSR2-dependent signaling in normal and malignant tissues. Disruption of KSR2 in SCLC-A cell lines inhibits the colony-forming ability of tumor-propagating cells in vitro and their tumor-initiating capacity in vivo. The effect of KSR2 depletion on self-renewal and clonogenicity is dependent on the interaction of KSR2 with ERK. These data indicate that the expression of KSR2 is an essential driver of SCLC-A tumor-propagating cell function and therefore may play a role in SCLC tumor initiation. These findings shed light on a novel effector promoting initiation of SCLC-A tumors and a potential subtype-specific therapeutic target.</p><p><strong>Implications: </strong>Manipulation of the molecular scaffold KSR2 in SCLC-A cells reveals its contribution to self-renewal, clonogenicity, and tumor initiation.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"640-652"},"PeriodicalIF":4.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12221803/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143597417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Empty Spiracles Homeobox 2 Transcription Factor Functions as a Tumor Suppressor in Renal Cell Carcinoma by Targeting CADM1.","authors":"Zhibin Fu, Wenqi Chen, Di Gu, Juan Li, Kai Dong, Yuying Lan, Tao Liu, Bianhong Zhang, Lei Li, Ethan Lee, Chenghua Yang, Tao P Zhong, Linhui Wang","doi":"10.1158/1541-7786.MCR-24-0496","DOIUrl":"10.1158/1541-7786.MCR-24-0496","url":null,"abstract":"<p><p>Renal cell carcinoma (RCC), a prevalent urinary system malignancy, often metastasizes at an early stage. Characterized by a complex pathogenesis and high mortality rate, RCC poses a significant clinical challenge. We evaluated the expression level of empty spiracles homeobox 2 (EMX2) in patients with RCC and revealed a significant reduction of EMX2 expression, correlating with a poor prognosis in patients with RCC. EMX2 functions as a tumor suppressor and inhibits RCC cell proliferation and migration, accompanied by programmed cell death. Implantation of EMX2-transduced RCC cells beneath the mouse kidney capsule or subcutaneous injection of transduced RCC cells results in a reduction in tumor growth and size. Through RNA sequencing and chromatin immunoprecipitation sequencing analyses, we have identified cell adhesion molecule 1 (CADM1) as a direct transcriptional target of EMX2's suppressive effects. CADM1 induction by EMX2 triggers PARP1-mediated parthanatos, a specific type of cell death due to mitochondrial oxidation reduction, in migrating RCC cells. Concurrently, EMX2-CADM1 upregulation instigates caspase-3-dependent apoptosis in attached RCC cells. Furthermore, the EMX2-CADM1 transcriptional axis also inhibits the PI3K-AKT pathway to impair RCC cell growth. Hence, the orchestrated effects mediated by the EMX2-CADM1 axis promote RCC cell death and suppress its growth and invasion, providing potential intervention strategies for combating RCC.</p><p><strong>Implications: </strong>The EMX2-CADM1 transcriptional axis offers a promising therapeutic target for inducing cell death and inhibiting growth and invasion in RCC, which could lead to more effective treatment strategies for this aggressive malignancy.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"597-610"},"PeriodicalIF":4.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143648176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SIRT2 Regulates the SMARCB1 Loss-Driven Differentiation Block in ATRT.","authors":"Irina Alimova, Dong Wang, John DeSisto, Etienne Danis, Senthilnath Lakshmanachetty, Eric Prince, Gillian Murdock, Angela Pierce, Andrew Donson, Ilango Balakrishnan, Natalie Serkova, Hening Lin, Nicholas K Foreman, Nathan Dahl, Sujatha Venkataraman, Rajeev Vibhakar","doi":"10.1158/1541-7786.MCR-24-0926","DOIUrl":"10.1158/1541-7786.MCR-24-0926","url":null,"abstract":"<p><p>An atypical teratoid rhabdoid tumor (ATRT) is a highly aggressive pediatric brain tumor driven by the loss of SMARCB1, which results in epigenetic dysregulation of the genome. SMARCB1 loss affects lineage commitment and differentiation by controlling gene expression. We hypothesized that additional epigenetic factors cooperate with SMARCB1 loss to control cell self-renewal and drive ATRT. We performed an unbiased epigenome-targeted screen to identify genes that cooperate with SMARCB1 and identified SIRT2 as a key regulator. Using in vitro pluripotency assays combined with in vivo single-cell RNA transcriptomics, we examined the impact of SIRT2 on differentiation of ATRT cells. We used a series of orthotopic murine models treated with SIRT2 inhibitors to examine the impact on survival and clinical applicability. We found that ATRT cells are highly dependent on SIRT2 for survival. Genetic or chemical inhibition led to decreased cell self-renewal and induction of differentiation in tumor spheres and in vivo models. We found that SIRT2 inhibition can restore gene expression programs lost because of SMARCB1 loss and reverse the differentiation block in ATRT in vivo. Finally, we showed the in vivo efficacy of a clinically relevant inhibitor demonstrating SIRT2 inhibition as a potential therapeutic strategy. We concluded that SIRT2 is a critical dependency in SMARCB1-deficient ATRT cells and acts by controlling the pluripotency-differentiation switch. Thus, SIRT2 inhibition is a promising therapeutic approach that warrants further investigation and clinical development.</p><p><strong>Implications: </strong>SIRT2 inhibition is a molecular vulnerability in SMARCB1-deleted tumors.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"515-529"},"PeriodicalIF":4.1,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12133431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extrachromosomal DNA Dynamics Contribute to Intratumoral Receptor Tyrosine Kinase Genetic Heterogeneity and Drug Resistance in Gastric Cancer.","authors":"Kazuki Kanayama, Hiroshi Imai, Ryotaro Hashizume, Chise Matsuda, Eri Usugi, Yoshifumi S Hirokawa, Masatoshi Watanabe","doi":"10.1158/1541-7786.MCR-24-0741","DOIUrl":"10.1158/1541-7786.MCR-24-0741","url":null,"abstract":"<p><p>Chromosomal instability in gastric cancer cells is associated with the amplification of oncogenes that encode receptor tyrosine kinases (RTK), such as HER2 and FGFR2; such gene amplification varies from cell to cell and manifests as genetic heterogeneity within tumors. The intratumoral genetic heterogeneity of RTK gene amplification causes heterogeneity in RTK protein expression, which has been suggested to be associated with therapeutic resistance to RTK inhibitors; however, the underlying mechanism is not fully understood. In this study, we show that extrachromosomal DNA (ecDNA) causes intratumoral genetic heterogeneity in RTKs and drug resistance due to diverse dynamic changes. We analyzed the dynamics of FGFR2 and MYC ecDNA in a gastric cancer cell line after single-cell cloning. Similar to those in parental cells, the copy numbers of FGFR2 and MYC in subclones differed significantly between cells, indicating intraclonal genetic heterogeneity. Furthermore, the ecDNA composition differed between subclones, which affected FGFR2 protein expression and drug sensitivity. Interestingly, clone cells that were resistant to the FGFR2 inhibitor AZD4547 presented diverse changes in ecDNA, including chimeric ecDNA, large ecDNA, and increased ecDNA numbers; these changes were associated with high expression and rephosphorylation of FGFR2. Conversely, when resistant clone cells were cultured under conditions that excluded AZD4547, the ecDNA status became similar to that of the original clone cells, and the inhibitory effect on cell growth was restored.</p><p><strong>Implications: </strong>Our results show that dynamic quantitative and qualitative changes in ecDNA can drive the intratumoral genetic heterogeneity of RTKs and resistance to RTK inhibitors.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"503-514"},"PeriodicalIF":4.1,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring STEAP1 Expression in Prostate Cancer Cells in Response to Androgen Deprivation and in Small Extracellular Vesicles.","authors":"Candice L Bizzaro, Camila A Bach, Ricardo A Santos, Cecilia E Verrillo, Nicole M Naranjo, Ishan Chaudhari, Francis J Picone, Waleed Iqbal, Ada G Blidner, Gabriel A Rabinovich, Alessandro Fatatis, Justine Jacobi, David W Goodrich, Kevin K Zarrabi, Wm Kevin Kelly, Matthew J Schiewer, Lucia R Languino","doi":"10.1158/1541-7786.MCR-24-0903","DOIUrl":"10.1158/1541-7786.MCR-24-0903","url":null,"abstract":"<p><p>The six-transmembrane epithelial antigen of the prostate (STEAP; STEAP1 and STEAP2) metalloreductases are therapeutic targets for advanced prostate cancer, and their expression has been linked to androgen receptor (AR) signaling; however, the regulatory mechanism and functions of STEAP1 and STEAP2 in prostate cancer progression remain elusive. In this study, we explore how in vitro androgen modulation and AR inhibition influence the expression of STEAP family members in cell lines with varying reliance on androgen signaling. Our data show that in response to androgen deprivation, STEAP1 and STEAP2 exhibit elevated transcript levels, whereas STEAP4 levels are reduced, mirroring the expression profile of kallikrein-related peptidase 3 (KLK3). As STEAP1 and STEAP2 are implicated in the exocytic pathway, we evaluated expression profiles in small extracellular vesicles (sEV) released from prostate cancer cells and in circulating sEVs. STEAP1, but not STEAP2, is upregulated in sEVs from AR-negative cells, which express low cellular STEAP1, and AR-positive cells, which express high cellular STEAP1. These results indicate selective packaging of STEAP1 in prostate cancer cell-derived sEVs, irrespective of AR status and cellular STEAP1 expression levels. Finally, ex vivo analysis of circulating sEVs from genetically engineered mice carrying prostate cancer shows that STEAP1 is found in the sEV cargo and that its levels are independent of protumorigenic β1 integrin expression in the prostatic epithelium.</p><p><strong>Implications: </strong>Understanding how androgen dependence affects STEAP1 expression in both tumor cells and sEVs across distinct disease stages will illuminate the clinical benefit of combinatorial AR and STEAP1-directed therapies and inform the optimal placement of STEAP1 targeting within the prostate cancer disease continuum.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"542-552"},"PeriodicalIF":4.1,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12133427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144064165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insulin Resistance Increases TNBC Aggressiveness and Brain Metastasis via Adipocyte-Derived Exosomes.","authors":"Yuhan Qiu, Andrew Chen, Rebecca Yu, Pablo Llevenes, Michael Seen, Naomi Y Ko, Stefano Monti, Gerald V Denis","doi":"10.1158/1541-7786.MCR-24-0494","DOIUrl":"10.1158/1541-7786.MCR-24-0494","url":null,"abstract":"<p><p>Patients with triple-negative breast cancer (TNBC) and comorbid type 2 diabetes (T2D), characterized by insulin resistance of adipose tissue, have a higher risk of metastasis and shorter survival. Adipocytes are the main nonmalignant cells of the breast tumor microenvironment (TME). However, adipocyte metabolism is usually ignored in oncology, and the mechanisms that couple T2D to TNBC outcomes are poorly understood. In this study, we hypothesized that exosomes, small vesicles secreted by TME breast adipocytes, drive epithelial-to-mesenchymal transition (EMT) and metastasis in TNBC via miRNAs. Exosomes were purified from conditioned media of 3T3-L1 mature adipocytes, either insulin-sensitive (IS) or insulin-resistant (IR). Murine 4T1 cells, a TNBC model, were treated with exosomes in vitro (72 hours). EMT, proliferation, and angiogenesis were elevated in IR versus control and IS. Brain metastases showed more mesenchymal morphology and EMT enrichment in the IR group. MiR-145a-3p is highly differentially expressed between IS and IR and potentially regulates metastasis.</p><p><strong>Implications: </strong>IR adipocyte exosomes modify the TME, enhance EMT, and promote brain metastasis-likely via miRNA pathways-suggesting that metabolic diseases such as T2D foster a prometastatic TME, reducing survival and warranting close monitoring and potential metabolic interventions in patients with TNBC and T2D.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"567-578"},"PeriodicalIF":4.1,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12133429/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KSR1 Mediates Small Cell Lung Carcinoma Tumor Initiation and Cisplatin Resistance.","authors":"Deepan Chatterjee, Robert A Svoboda, Dianna H Huisman, Benjamin J Drapkin, Heidi M Vieira, Chaitra Rao, James W Askew, Kurt W Fisher, Robert E Lewis","doi":"10.1158/1541-7786.MCR-24-0652","DOIUrl":"10.1158/1541-7786.MCR-24-0652","url":null,"abstract":"<p><p>Small cell lung cancer (SCLC) has a dismal 5-year survival rate of less than 7%, with limited advances in first-line treatment over the past four decades. Tumor-initiating cells (TIC) contribute to resistance and relapse, a major impediment to SCLC treatment. In this study, we identify kinase suppressor of Ras 1 (KSR1), a molecular scaffold for the Raf/MEK/ERK signaling cascade, as a critical regulator of SCLC TIC formation and tumor initiation in vivo. We further show that KSR1 mediates cisplatin resistance in SCLC. Whereas 50% to 70% of control cells show resistance after 6-week exposure to cisplatin, CRISPR/Cas9-mediated KSR1 knockout prevents resistance in >90% of SCLC cells in ASCL1, NeuroD1, and POU2F3 subtypes. KSR1 knockout significantly enhances the ability of cisplatin to decrease SCLC TICs via in vitro extreme limiting dilution analysis, indicating that KSR1 disruption enhances the cisplatin toxicity of cells responsible for therapeutic resistance and tumor initiation. The ability of KSR1 disruption to prevent cisplatin resistance in H82 tumor xenograft formation supports this conclusion. Previous studies indicate that ERK activation inhibits SCLC tumor growth and development. We observe a minimal effect of pharmacologic ERK inhibition on cisplatin resistance and no impact on TIC formation via in vitro extreme limiting dilution analysis. However, mutational analysis of the KSR1 DEF domain, which mediates interaction with ERK, suggests that ERK interaction with KSR1 is essential for KSR1-driven cisplatin resistance. These findings reveal KSR1 as a key regulatory protein in SCLC biology and a potential therapeutic target across multiple SCLC subtypes.</p><p><strong>Implications: </strong>Genetic manipulation of the molecular scaffold KSR1 in SCLC cells reveals its contribution to cisplatin resistance and tumor initiation.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"553-566"},"PeriodicalIF":4.1,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12133430/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Bridging Role of Schwann Cells in the Interaction between Tumors and the Nervous System: A Potential Target for Cancer Therapy.","authors":"Yonghui Zhang, Ye Yuan, Ying Wang, Zhixin Ye, Ting Liu, Guangming Lv, Gang Chen","doi":"10.1158/1541-7786.MCR-25-0124","DOIUrl":"10.1158/1541-7786.MCR-25-0124","url":null,"abstract":"<p><p>Nerves are important components of the tumor microenvironment and can regulate the progression of various solid tumors. Tumor innervation (TIN) and perineural invasion (PNI) are the two main modes of interaction between tumors and the nervous system. The former simulates neurogenesis or axonogenesis during neural development, whereas the latter causes neuroinflammation during nerve injury. As the principal glial cells of the peripheral nervous system, Schwann cells (SC) are easily hijacked and utilized by cancer cells due to their high plasticity and versatility. Whether TIN or PNI occurs in a tumor, SCs are believed to be associated with these processes, which indicate that SCs may be a target for cancer neurotherapy. This review focuses on elucidating the interactions between tumors and the peripheral nervous system and the underlying mechanisms involved. Specifically, we delineated the pivotal role of SCs in TIN, PNI, cancer pain, and the immunosuppressive microenvironment. Furthermore, we compared the advantages and disadvantages of several preclinical trials that have exploited the nervous system to treat cancer and discussed the importance of SCs as a new target in cancer neuroscience research. We hope that this review will contribute to a deeper understanding of the significant involvement of SCs within the tumor-neuroimmune axis and provide novel insights for innovative antitumor therapies.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"494-502"},"PeriodicalIF":4.1,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}